Effect of human recombinant erythropoietin therapy on panel reactive antibodies in chronic dialysis patients

To examine whether recombinant human erythropoietin (rhEPO) therapy results in decreased presensitization to foreign HLA antigens, we retrospectively analyzed data from 64 of 200 patients treated in a university hospital dialysis center between 1985 and 1995 who had undergone routine panel reactive antibody (PRA%) screening. Though a significant decrease in the annual frequency of highly sensitized patients over the years was noted, 16 patients followed for 27.1 +/- 3.7 months after initiation of rhEPO therapy until transplantation or blood transfusion showed no significant overall decrease in PRA%. Six highly presensitized patients had moderate but significant overall decrease in PRA%. However, in three of these patients the PRA% was unchanged and in the other three patients the PRA% remained over 50%. Thus rhEPO therapy reduced the incidence of highly presensitized patients, but previously presensitized patients remained presensitized. We conclude that removal of transfusional stimulation of lymphocytotoxic antibody production does not appear to benefit previously presensitized patients, possibly due to the maintenance of B-lymphocyte clonal expansion by unknown factors, or even by rhEPO itself.     

Pharmacological effects of propylthiouracil on corticosterone secretion in male rats

BACKGROUND: We investigated the direct effects of propylthiouracil (PTU) on corticosterone secretion both in vivo and in vitro. METHODS: Male rats were divided into 4 groups and then injected subcutaneously with saline, PTU, PTU plus thyroxine (T4), or T4 once daily for 2 weeks. After 2 weeks, rats were decapitated or received adrenocorticotropic hormone (ACTH), intravenously. Zona fasciculata-reticularis (ZFR) cells from normal, saline-, PTU-, PTU plus T4-, or T4-treated rats were incubated with ACTH, forskolin, 8-Br-cAMP, deoxycorticosterone (DOC) +/- PTU (1, 2, or 5 mg/mL) at 37 degrees C for 2 hours. Corticosterone concentrations in plasma and cell media, and 3':5'-cyclic adenosine monophosphate (cAMP) production in ZFR cells were determined by radioimmunoassay. The effects of PTU on the activities of steroidogenic enzymes in ZFR cells were measured by the amounts of intermediate steroidal products separated by thin-layer chromatography. RESULTS: The basal and ACTH-stimulated levels of plasma corticosterone in PTU-treated rats were lower as compared to saline-treated animals. Both basal and ACTH-stimulated corticosterone secretion were inhibited by PTU > 2 mg/mL in rat ZFR cells. The cAMP production induced by forskolin was lower in PTU, PTU plus T4, or T4-treated rats than in saline-treated animals. Chronic administration of PTU or PTU plus T4 inhibited the 3 beta-hydroxysteroid dehydrogenase, 21 beta-hydroxylase, and 11 beta-hydroxylase activities. Administration of PTU (1, 2, and 5 mg/mL) suppressed the basal, ACTH, 8-Br-cAMP, forskolin, and DOC-stimulated corticosterone secretion in rat ZFR cells. Likewise, PTU > 2 mg/mL inhibited the ACTH and 8-Br-cAMP-stimulated levels of intracellular cAMP in rat ZFR cells. CONCLUSIONS: These results suggest that PTU counteracts both basal and ACTH-induced adrenal steroidogenesis through their attenuation of the activity of 11 beta-hydroxylase and cAMP production in rat ZFR cells.     

Gene therapy for hemophilia: feasible in principle but not yet clinically applicable]

The current treatment of haemophiliacs consists of injection of concentrates of blood clotting factors VIII (haemophilia A) and IX (haemophilia B). The inconvenience of the multiple injections needed, and the risk of transmission of infectious agents (HIV, hepatitis) prompted the development of alternative therapies. Gene therapy aims at introducing functional factor VIII and IX genes into the body cells of patients in order to make these cells produce the desired clotting factors. There are two strategies for gene therapy: (a) in the laboratory cells of the patient may be provided with the desired gene, followed by reintroduction of the cells that now produce factor VIII, into the patient (ex vivo strategy); (b) vectors with the desired genes may be injected into the patient in order to induce the modification (in vivo strategy) For both routes, the formal proof-of-principle has been acquired recently in animal experiments: cells modified by factor VIII or IX genes will produce adequate concentrations of the clotting products in plasma and will correct the bleeding tendency. Before the clinical evaluation and widespread application of the technology can be considered many technical problems have to be solved.     

Intra-articular calcaneal fractures: effect of open reduction and internal fixation on the contact characteristics of the subtalar joint

Intra-articular calcaneal fractures are associated with significant long-term morbidity, and considerable controversy exists regarding the optimum method of treating them. The contact characteristics in the intact subtalar joint were determined at known loads and for different positions of the ankle and subtalar joint, using pressure-sensitive film (Super Low; Fuji, Itochu Canada Ltd, Montreal, Quebec). We measured the contact area to joint area ratio (pressure > 5 kg force/cm2 [kgf/cm2]) which normalizes for differences in joint size and the ratio of high pressure zone (>20 kgf/cm2) as a reflection of overall increase in joint pressure. Three simulated fracture patterns were then created and stabilized with either 1 or 2 mm of articular incongruity. Eight specimens were prepared with a primary fracture line through the posterior facet, eight with a joint depression-type fracture, and six with a central joint depression fracture. A measure of 1 to 2 mm of incongruity in the posterior facet for all three fracture patterns produced significant unloading of the depressed fragment, with a redistribution of the overall pattern of pressure distribution to parts of the facet that were previously unloaded.     

Antenatal glucocorticoid administration increases corticotrophin-releasing hormone in maternal plasma

OBJECTIVES: To examine associations between medical and functional variables and at-fault car crashes in a cohort of older drivers. DESIGN: A case-control study. SETTING: A tertiary care medical center. PARTICIPANTS: Older drivers (ages 55-90 years) residing in Jefferson County, Alabama (n = 174). Cases were drivers who had at least one at-fault crash in the previous 6 years; controls were crash-free during the same period. MEASUREMENTS: Self-reported medical conditions, reported and observed functional measures, and urinary drug screens. The occurrence of one or more at-fault car crashes in the 6 years preceding the 1991 assessment date represented the outcome measure. RESULTS: Ninety-nine older drivers experienced between one and seven at-fault vehicle crashes during the period 1985 through 1991, whereas 75 drivers did not. Logistic regression models indicated that the following variables were independently associated with crash involvement: A 40% or greater reduction in the useful field of view (OR = 6.1; 95% CI, 2.9 to 12.7; P < 0.001), black race (OR = 6.6; 95% CI, 1.7 to 26.2; P = .007), a history of falling in the previous 2 years (OR = 2.6; CI, 1.1 to 6.1; P = .025), and not taking a beta-blocking drug (OR = 4.3; CI, 1.2 to 15.0; P = .023). CONCLUSIONS: Functional assessments, such as a comprehensive test of visual processing, a falls history, and a review of current medications may be of greater relevance than specific medical conditions in the identification of older at-risk drivers. If prospective studies determine that falling and crashing share risk factors, a unified approach to the prevention of these mobility disorders could result. The finding of an independent association of black race with at-fault crashing is in need of further clarification because of the low representation of black drivers in this sample.     

Synthesis of a potent wide-spectrum serotonin-, norepinephrine-, dopamine-reuptake inhibitor (SNDRI) and a species-selective dopamine-reuptake inhibitor based on the gamma-amino alcohol functional group

Mortality data for B6CF1 mice exposed to 60Co gamma rays for the duration of life were used to make quantitative predictions of age-specific mortality observed in comparably exposed beagles. Simple Kaplan-Meier survival curves for the beagles and their 95% confidence intervals were computed for each dose-rate group observed. A dose-response equation was estimated from the mortality data for mice using a proportional hazard model. The dose-response model for mice was then used to generate predicted survivorship curves at dose rates that would recreate the dose burdens observed in the beagle at comparable points within the life span of the two organisms. When these predicted survivorship curves were scaled to adjust for species differences in the life span of control animals, the predictions for the mouse fell within the confidence intervals observed for the beagle. The successful interspecies extrapolation of age-specific mortality risks for species as different as the mouse and dog enhances both the value of studies involving laboratory animals and the potential relevance of the animal studies to the prediction of health effects in humans.     

Efficacy of azithromycin in the treatment of cyclosporine-induced gingival hyperplasia in renal transplant recipients

BACKGROUND: Gingival hyperplasia (GH) is a common side effect of cyclosporine . Azithromycin (Zithromax; AZI) is a macrolide antibiotic reported in case studies to reduce cyclosporine-induced gingival hyperplasia (CIGH) in renal transplant recipients (RTR). METHODS: The efficacy of AZI to treat CIGH in RTR was examined in a double-blind, randomized crossover trial. Patients (n=17) with CIGH were randomized to receive AZI and a matching placebo in alternate order for 5 days, separated by a 2-week washout period. Follow-up visits were conducted at week 6 and week 12. Changes in GH were evaluated by measuring the clinical gingival sulcus depths, tooth length, and the length of the interdental papillae to the cementum-enamel junction of two teeth in each of the four quadrants. RESULTS: Significant improvements were observed in all three types of periodontal measurements, representing reductions of gingival tissue above the medial aspect of the tooth, of the gingival sulcus depth, and of the length of the interdental papillae. Patients reported an improvement in gum bleeding. AZI was well tolerated, and 67% of the patients reported that the treatment was at least somewhat useful. CONCLUSIONS: AZI should be considered for RTR with CIGH.     

Size- and invasion-dependent increase in cyclooxygenase 2 levels in human colorectal carcinomas

Nonsteroidal anti-inflammatory drugs reduce the incidence and mortality of colorectal carcinoma. Their chemopreventive effects appear to be due to inhibition of cyclooxygenase (COX)-2. Here, we have studied the relationship between the COX-2 mRNA levels and pathological characteristics in 43 primary colorectal carcinomas. COX-2 levels were significantly higher in tumors with larger sizes and in those with deeper invasions but were not correlated with whether the patients had metastasis or not. These results suggest that larger carcinomas produce more COX-2 to support their own growth and that COX-2 inhibitors may be effective agents of carcinoma growth suppression.